Pentafluorobenzenesulfonamides and analogs

ABSTRACT

The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, vascular restenosis, microbial infections, and psoriasis, or as lead compounds for the development of such agents. The compositions include compounds of the general formula I:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/896,280, filed Jul. 18, 1997 now U.S. Pat. No. 6,482,860, and claimsbenefit of U.S. Provisional Application No. 60/022,198, filed Jul. 19,1996, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The field of the invention is pentafluorobenzenesulfonamide derivativesand analogs and their use as pharmacologically active agents.

BACKGROUND

A number of human diseases stem from processes of uncontrolled orabnormal cellular proliferation. Most prevalent among these is cancer, ageneric name for a wide range of cellular malignancies characterized byunregulated growth, lack of differentiation, and the ability to invadelocal tissues and metastasize. These neoplastic malignancies affect,with various degrees of prevalence, every tissue and organ in the body.A multitude of therapeutic agents have been developed over the past fewdecades for the treatment of various types of cancer. The most commonlyused types of anticancer agents include: DNA-alkylating agents (e.g.,cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, afolate antagonist, and 5-fluorouracil, a pyrimidine antagonist),microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNAintercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormonetherapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drugwould kill cancer cells selectively, with a wide therapeutic indexrelative to its toxicity towards non-malignant cells. It would alsoretain its efficacy against malignant cells even after prolongedexposure to the drug. Unfortunately, none of the current chemotherapiespossess an ideal profile. Most possess very narrow therapeutic indexes,and in practically every instance cancerous cells exposed to slightlysublethal concentrations of a chemotherapeutic agent will developresistance to such an agent, and quite often cross-resistance to severalother antineoplastic agents.

Psoriasis, a common chronic skin disease characterized by the presenceof dry scales and plaques, is generally thought to be the result ofabnormal cell proliferation. The disease results from hyperproliferationof the epidermis and incomplete differentiation of keratinocytes.Psoriasis often involves the scalp, elbows, knees, back, buttocks,nails, eyebrows, and genital regions, and may range in severity frommild to extremely debilitating, resulting in psoriatic arthritis,pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeuticcure exists for psoriasis. Milder cases are often treated with topicalcorticosteroids, but more severe cases may be treated withantiproliferative agents, such as the antimetabolite methotrexate, theDNA synthesis inhibitor hydroxyurea, and the microtubule disruptercolchicine.

Other diseases associated with an abnormally high level of cellularproliferation include restenosis, where vascular smooth muscle cells areinvolved, inflammatory disease states, where endothelial cells,inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.bacteria, trypanosomes, fungi, etc) are also subject to selectiveproliferative control using the subject compositions and compounds.

Accordingly, it is one object of the present invention to providecompounds which directly or indirectly are toxic to actively dividingcells and are useful in the treatment of cancer, viral and bacterialinfections, vascular restenosis, inflammatory diseases, autoimmunediseases, and psoriasis.

A further object of the present invention is to provide therapeuticcompositions for treating said conditions.

Still further objects are to provide methods for killing activelyproliferating cells, such as cancerous, bacterial, or epithelial cells,and treating all types of cancers, infections, inflammatory, andgenerally proliferative conditions. A further object is to providemethods for treating other medical conditions characterized by thepresence of rapidly proliferating cells, such as psoriasis and otherskin disorders.

Other objects, features and advantages will become apparent to thoseskilled in the art from the following description and claims.

SUMMARY OF THE INVENTION

The invention provides methods and compositions relating to novelpentafluorophenylsulfonamide derivatives and analogs and their use aspharmacologically active agents. The compositions find particular use aspharmacological agents in the treatment of disease states, particularlycancer, bacterial infections and psoriasis, or as lead compounds for thedevelopment of such agents.

In one embodiment, the invention provides for the pharmaceutical use ofcompounds of the general formula I and for pharmaceutically acceptablecompositions of compounds of formula I:

or a physiologically acceptable salt thereof, wherein:

-   Y is —S(O)— or —S(O)₂—;-   Z is —NR¹R² or —OR³, where R¹ and R² are independently selected from    hydrogen,-   substituted or unsubstituted (C1-C10)alkyl,-   substituted or unsubstituted (C1-C10)alkoxy,-   substituted or unsubstituted (C3-C6)alkenyl,-   substituted or unsubstituted (C2-C6)heteroalkyl,-   substituted or unsubstituted (C3-C6)heteroalkenyl,-   substituted or unsubstituted (C3-C6)alkynyl,-   substituted or unsubstituted (C3-C8)cycloalkyl,-   substituted or unsubstituted (C5-C7)cycloalkenyl,-   substituted or unsubstituted (C5-C7)cycloalkadienyl,-   substituted or unsubstituted aryl,-   substituted or unsubstituted aryloxy,-   substituted or unsubstituted aryl-(C3-C8)cycloalkyl,-   substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,-   substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,-   substituted or unsubstituted aryl-(C1-C4)alkyl,-   substituted or unsubstituted aryl-(C1-C4)alkoxy,-   substituted or unsubstituted aryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted aryl-(C3-C6)alkenyl,-   substituted or unsubstituted aryloxy-(C1-C4)alkyl,-   substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl,-   substituted or unsubstituted heteroaryloxy,-   substituted or unsubstituted heteroaryl-(C1-C4)alkyl,-   substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,-   substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,-   substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and-   substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,    wherein R¹ and R² may be connected by a linking group E to give a    substituent of the formula    wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)    heteroalkylene, and the ring formed by R¹, E, R² and the nitrogen    contains no more than 8 atoms, or preferably the R¹ and R² may be    covalently joined in a moiety that forms a 5- or 6-membered    heterocyclic ring with the nitrogen atom of NR¹R²;    and where R³ is a substituted or unsubstituted aryl or heteroaryl    group.

Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienylradicals are selected independently from

-   —H-   —OH-   —O—(C1-C10)alkyl-   ═O-   —NH₂-   —NH—(C1-C10)alkyl-   —N[(C1-C10)alkyl]₂-   —SH-   —S—(C1-C10)alkyl-   -halo-   —Si[(C1-C10)alkyl]₃    in a number ranging from zero to (2N+1), where N is the total number    of carbon atoms in such radical.

Substituents for the aryl and heteroaryl groups are selectedindependently from

-   -halo-   —OH-   —O—R′-   —O—C(O)—R′-   —NH₂-   —NHR′-   —NR′R″-   —SH-   —SR′-   —R′-   —CN-   —NO₂-   —CO₂H-   —CO₂—R′-   —CONH₂-   —CONH—R′-   —CONR′R″-   —O—C(O)—NH—R′-   —O—C(O)—NR′R″-   —NH—C(O)—R′-   —NR″—C(O)—R′-   —NH—C(O)—OR′-   —NR″—C(O)—R′-   —NH—C(NH₂)═NH-   —NR′—C(NH₂)═NH-   —NH—C(NH₂)═NR′-   —S(O)—R′-   —S(O)₂—R′-   —S(O)₂—NH—R′-   —S(O)₂—NR′R″-   —N₃-   —CH(Ph)₂-   substituted or unsubstituted aryloxy-   substituted or unsubstituted arylamino-   substituted or unsubstituted heteroarylamino-   substituted or unsubstituted heteroaryloxy-   substituted or unsubstituted aryl-(C1-C4)alkoxy,-   substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,-   perfluoro(C1-C4)alkoxy, and-   perfluoro(C1-C4)alkyl,    in a number ranging from zero to the total number of open valences    on the aromatic ring system;    and where R′ and R″ are independently selected from:-   substituted or unsubstituted (C1-C10)alkyl,-   substituted or unsubstituted (C1-C10)heteroalkyl,-   substituted or unsubstituted (C2-C6)alkenyl,-   substituted or unsubstituted (C2-C6)heteroalkenyl,-   substituted or unsubstituted (C2-C6)alkynyl,-   substituted or unsubstituted (C3-C8)cycloalkyl,-   substituted or unsubstituted (C3-C8)heterocycloalkyl,-   substituted or unsubstituted (C5-C6)cycloalkenyl,-   substituted or unsubstituted (C5-C6)cycloalkadienyl,-   substituted or unsubstituted aryl,-   substituted or unsubstituted aryl-(C1-C4)alkyl,-   substituted or unsubstituted aryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted aryl-(C2-C6)alkenyl,-   substituted or unsubstituted aryloxy-(C1-C4)alkyl,-   substituted or unsubstituted aryloxy-(C1-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl,-   substituted or unsubstituted heteroaryl-(C1-C4)alkyl,-   substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl-(C2-C6)alkenyl,-   substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and-   substituted or unsubstituted heteroaryloxy-(C1-C4)heteroalkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula—T—C(O)—(CH₂)_(n)—U—, wherein T and U are independently selected from N,O, and C, and n=0-2. Alternatively, two of the substituents on adjacentatoms of the aryl or heteroaryl ring may optionally be replaced with asubstituent of the formula —A—(CH2)p-B—, wherein A and B areindependently selected from C, O, N, S, SO, SO₂, and SO₂NR′, and p=1-3.One of the single bonds of the new ring so formed may optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula —(CH₂)_(q)—X—(CH₂)_(r)—, where q and rare independently 1-3, and X is selected from O, N, S, SO, SO₂ andSO₂NR′. The substituent R′ in SO₂NR′ is selected from hydrogen or(C1-C6)alkyl.

In another embodiment, the invention provides novel methods for the useof pharmaceutical compositions containing compounds of the foregoingdescription of the general formula I. The invention provides novelmethods for treating pathology such as cancer, bacterial infections andpsoriasis, including administering to a patient an effective formulationof one or more of the subject compositions.

In another embodiment, the invention provides chemically-stable,pharmacologically active compounds of general formula I:

or a pharmaceutically acceptable salt thereof, wherein:Y is —S(O)— or —S(O₂)—; andZ is NR¹R², wherein R² is an optionally substituted aryl or heteroarylgroup, and R¹ is selected from:

-   hydrogen,-   substituted or unsubstituted (C1-C10)alkyl,-   substituted or unsubstituted (C1-C10)alkoxy,-   substituted or unsubstituted (C3-C6)alkenyl,-   substituted or unsubstituted (C2-C6)heteroalkyl,-   substituted or unsubstituted (C3-C6)heteroalkenyl,-   substituted or unsubstituted (C3-C6)alkynyl,-   substituted or unsubstituted (C3-C8)cycloalkyl,-   substituted or unsubstituted (C5-C7)cycloalkenyl,-   substituted or unsubstituted (C5-C7)cycloalkadienyl,-   substituted or unsubstituted aryl,-   substituted or unsubstituted aryloxy,-   substituted or unsubstituted aryl-(C3-C8)cycloalkyl,-   substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,-   substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,-   substituted or unsubstituted aryl-(C1-C4)alkyl,-   substituted or unsubstituted aryl-(C1-C4)alkoxy,-   substituted or unsubstituted aryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted aryl-(C3-C6)alkenyl,-   substituted or unsubstituted aryloxy-(C1-C4)alkyl,-   substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl,-   substituted or unsubstituted heteroaryloxy,-   substituted or unsubstituted heteroaryl-(C1-C4)alkyl,-   substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,-   substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,-   substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,-   substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and-   substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,    wherein R¹ and R² may be connected by a linking group E to give a    substituent of the formula    wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)    heteroalkylene, and the ring formed by R¹, E, R² and the nitrogen    contains no more than 8 atoms, or preferably the R¹ and R² may be    covalently joined in a moiety that forms a 5- or 6-membered    heterocyclic ring with the nitrogen atom of NR¹R²;    provided that:

in the case that Y is —S(O₂)—, and R¹ is hydrogen or methyl, then R² issubstituted phenyl or heteroaryl group;

in the case that Y is —S(O₂)— and R² is a ring system chosen from1-naphthyl, 5-quinolyl, or 4-pyridyl, then either R¹ is not hydrogen orR² is substituted by at least one substituent that is not hydrogen;

in the case that Y is —S(O₂)—, R² is phenyl, and R¹ is a propylene unitattaching the nitrogen of —NR¹ R²— to the 2- position of the phenyl ringin relation to the sulfonamido group to form a1,2,3,4-tetrahydroquinoline system, one or more of the remainingvalences on the bicyclic system so formed is substituted with at leastone substituent that is not hydrogen;

in the case that Y is —S(O₂)— and R² is phenyl substituted with3-(1-hydroxyethyl), 3-dimethylamino, 4-dimethylamino, 4-phenyl,3-hydroxy, 3-hydroxy-4-diethylaminomethyl, 3,4-methylenedioxy,3,4-ethylenedioxy, 2-(1-pyrrolyl), or 2-methoxy-4-(1-morpholino), theneither R¹ is not hydrogen or when R¹ is hydrogen, one or more of theremaining valences on the phenyl ring of R² is substituted with asubstituent that is not hydrogen;

in the case that Y is —S(O₂)— and R² is 2-methylbenzothiazol-5-yl,6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl,5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl,3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl,2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 5,6,7,8-tetrahydro-2-naphthyl,4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl,7-chloro-5-methyl-1,8-naphthyridin-2-yl,5,7-dimethyl-1,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl, R¹ is agroup other than hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” by itself or as part of another substituent means,unless otherwise stated, a straight or branched chain hydrocarbonradical, including di- and multi-radicals, having the number of carbonatoms designated (i.e. C1-C10 means one to ten carbons) and includesstraight or branched chain groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomersof n-pentyl, n-hexyl, 2-methylpentyl, 1,5-dimethylhexyl,1-methyl-4-isopropylhexyl and the like. The term “alkylene” by itself oras part of another substituent means a divalent radical derived from analkane, as exemplified by —CH₂CH₂CH₂CH₂—. A “lower alkyl” is a shorterchain alkyl, generally having six or fewer carbon atoms.

The term “heteroalkyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainradical consisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include —O—CH₂—CH₂—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂—S(O)—CH₃, —O—CH₂—CH₂—CH₂—NH—CH₃, and —CH₂—CH₂—S(O)₂—CH₃. Up totwo heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂NH—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like.Examples of heterocycloalkyl include 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term “alkenyl” employed alone or in combination with other terms,means, unless otherwise stated, a stable straight chain or branchedmonounsaturated or diunsaturated hydrocarbon group having the statednumber of carbon atoms. Examples include vinyl, propenyl (allyl),crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by —CH═CH—CH₂—.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or diunsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quarternized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

The term “alkynyl” employed alone or in combination with other terms,means, unless otherwise stated, a stable straight chain or branchedhydrocarbon group having the stated number of carbon atoms, andcontaining one or two carbon-carbon triple bonds, such as ethynyl, 1-and 3-propynyl, 4-but-1-ynyl, and the higher homologs and isomers.

The term “alkoxy” employed alone or in combination with other terms,means, unless otherwise stated, an alkyl group, as defined above,connected to the rest of the molecule via an oxygen atom, such as, forexample, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologsand isomers.

The terms “halo” or “halogen” by themselves or as part of anothersubstituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The term “aryl” employed alone or in combination with other terms,means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthylgroup. The maximal number of substituents allowed on each one of thesering systems is five, seven, and seven, respectively. Substituents areselected from the group of acceptable substituents listed above.

The term “heteroaryl” by itself or as part of another substituent means,unless otherwise stated, an unsubstituted or substituted, stable, mono-or bicyclic heterocyclic aromatic ring system which consists of carbonatoms and from one to four heteroatoms selected from the groupconsisting of N, O, and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen atom mayoptionally be quaternized. The heterocyclic system may be attached,unless otherwise stated at any heteroatom or carbon atom which affords astable structure. The heterocyclic system may be substituted orunsubstituted with one to four substituents independently selected fromthe list of acceptable aromatic substituents listed above. Examples ofsuch heterocycles include 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl.

Pharmaceutically acceptable salts of the compounds of Formula I includesalts of these compounds with relatively nontoxic acids or bases,depending on the particular substituents found on specific compounds ofFormula I. When compounds of Formula I contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of compound I with a sufficient amount of the desired base,either neat or in a suitable inert solvent. Examples of pharmaceuticallyacceptable base addition salts include sodium, potassium, calcium,ammonium, organic amino, or magnesium salt, or a similar salt. Whencompounds of Formula I contain relatively basic functionalities, acidaddition salts can be obtained by contacting the neutral form ofcompound I with a sufficient amount of the desired acid, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like gluconic or galactunoric acids and the like(see, for example, Berge, S. M., et al, “Pharmaceutical Salts”, Journalof Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). Certain specificcompounds of Formula I contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

The free base form may be regenerated by contacting the salt with a baseor acid and isolating the parent compound in the conventional manner.The parent form of the compound differs from the various salt forms incertain physical properties, such as solubility in polar solvents, butotherwise the salts are equivalent to the parent form of the compoundfor the purposes of the present invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers); the racemates, diastereomers, and individualisomers are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium (³H)or carbon-14 (¹⁴C). All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

In various preferred embodiments of the pharmaceutical compositions ofcompounds of formula I, Y is S(O₂) and Z is NR¹R², wherein R¹ ishydrogen or methyl, and R² is a substituted phenyl, preferably mono-,di-, or trisubstituted as follows. In one group of preferred compounds,Y is S(O₂) and Z is NR¹R², wherein R¹ is hydrogen or methyl, and R² is aphenyl group, preferably substituted in the para position by one of thefollowing groups: hydroxy, amino, (C1-C10)alkoxy, (C1-C10)alkyl,(C1-C10)alkylamino, and [di(C1-C10)alkyl]amino, with up to fouradditional substituents independently chosen from hydrogen, halogen,(C1-C10)alkoxy, (C1-C10)alkyl, and [di(C1-C10)alkyl]amino. Alsopreferred are compounds of formula I where there is no linking group Ebetween R¹ and R².

Illustrative examples of pharmaceutical compositions and compounds ofthe subject pharmaceutical methods include:

-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene;-   4-Dimethylamino-1-pentafluorophenylsulfinamidobenzene;-   4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;-   4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;-   2-Pentafluorophenylsulfonamidothiophene;-   3-Pentafluorophenylsulfonamidothiophene;-   3-Pentafluorophenylsulfonamidopyridine;-   4-Pentafluorophenylsulfonamidopyridine;-   4-(N,N,-Dimethylamino)-1-(N-ethylpentafluorophenylsulfonamido)-benzene;-   4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;-   4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Hydroxy-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;-   1,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonylindole;-   1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;-   1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;-   1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;-   3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;-   4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Chloro-5-pentafluorophenylsulfonamidopyridine;-   2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;-   4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;-   3-Chloro-1-pentafluorophenylsulfonamidobenzene;-   4-Chloro-1-pentafluorophenylsulfonamidobenzene;-   3-Nitro-1-pentafluorophenylsulfonamidobenzene;-   4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;-   4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;-   1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;-   1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;-   1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;-   3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonamido-4-phenoxybenzene;-   6-Pentafluorophenylsulfonamidoquinoline;-   2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;-   5-Pentafluorophenylsulfonamidobenzo[a]thiophene;-   5-Pentafluorophenylsulfonamidobenzo[a]furan;-   3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;-   4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;-   4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene;-   2-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonamido-4-propoxybenzene;-   4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;-   1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;-   1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;-   4(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;-   4-Amino-1-pentafluorophenylsulfonamidobenzene;-   Pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamidoindazole;-   4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;-   1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;-   3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;-   7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;-   3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;-   4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;-   2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;-   1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;-   3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;-   3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;-   2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;-   4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene,    hydrochloride;-   2-Methoxy-5-pentafluorophenylsulfonamidopyridine; and-   2-Anilino-3-pentafluorophenylsulfonamidopyridine.

Examples of the most preferred pharmaceutical compositions and compoundsof the subject pharmaceutical methods include:

-   4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;-   3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;-   1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium    salt;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium    salt;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium    salt;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium    salt;-   4-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;-   4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamidoindole;-   4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;-   4-Chloro-1-pentafluorophenylsulfonamidobenzene; and-   3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.

The invention provides for certain novel compounds of general Formula Ithat possess one or more valuable biological activities such as apharmacologic, toxicologic, metabolic, etc.

Exemplary compounds of this embodiment of the invention include:

-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene;-   4-Dimethylamino-1-pentafluorophenylsulfinamidobenzene;-   4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;-   4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;-   2-Pentafluorophenylsulfonamidothiophene;-   3-Pentafluorophenylsulfonamidothiophene;-   3-Pentafluorophenylsulfonamidopyridine;-   4-Pentafluorophenylsulfonamidopyridine;-   4-(N,N,-Dimethylammonio)-1-(N-ethylpentafluorophenylsulfonamido)    benzene;-   4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;-   1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;-   1,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonylindole;-   1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;-   1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;-   1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;-   3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;-   4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Chloro-5-pentafluorophenylsulfonamidopyridine;-   2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;-   4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;-   3-Chloro-1-pentafluorophenylsulfonamidobenzene;-   4-Chloro-1-pentafluorophenylsulfonamidobenzene;-   3-Nitro-1-pentafluorophenylsulfonamidobenzene;-   4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;-   4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;-   1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;-   1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;-   1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;-   4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;-   3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Butoxy-1-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonamido-4-phenoxybenzene;-   4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;-   4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene;-   2-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;-   1-Pentafluorophenylsulfonamido-4-propoxybenzene;-   4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;-   1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;-   1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;-   4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;-   4-Amino-1-pentafluorophenylsulfonamidobenzene;-   Pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamidoindazole;-   4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;-   1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;-   3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;-   7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;-   3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;-   4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;-   2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;-   1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;-   4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;-   6-Pentafluorophenylsulfonamidoquinoline;-   2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;-   5-Pentafluorophenylsulfonamidobenzo[a]thiophene;-   5-Pentafluorophenylsulfonamidobenzo[a]furan;-   3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;-   3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;-   3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;-   2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;-   4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene,    hydrochloride; and,-   2-Anilino-3-pentafluorophenylsulfonamidopyridine.

Preferred compounds of this embodiment of the invention have specificpharmacological properties. Examples of the most preferred compounds ofthis embodiment of the invention include:

-   4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;-   3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;-   1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium    salt;-   2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium    salt;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium    salt;-   2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium    salt;-   4-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;-   4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;-   5-Pentafluorophenylsulfonamidoindole;-   4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;-   3-Methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;-   2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;-   2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;-   1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;-   4-Chloro-1-pentafluorophenylsulfonamidobenzene; and-   3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.    Synthesis

The invention provides methods of making the subject compounds andcompositions. In one general embodiment, the methods involve combiningpentafluorophenylsulfonyl chloride with an amine having the generalformula R¹R²NH under conditions whereby the pentafluorophenylsulfonylchloride and amine react to form the desired compound, and isolating thecompound.

Compounds with the generic structure 1 or 3 (Scheme I) may be preparedby reacting the appropriate starting amine in a solvent such astetrahydrofuran (THF), dimethylformamide (DMF), ether, toluene orbenzene in the presence of a base such as pyridine,p-dimethylaminopyridine, triethylamine, sodium carbonate or potassiumcarbonate and pentafluorophenylsulfonyl chloride orpentafluorophenylsulfinyl chloride, respectively. Pyridine itself mayalso be used as the solvent. Preferred solvents are pyridine and DMF andpreferred bases are pyridine, triethylamine, and potassium carbonate.This reaction can be carried out at a temperature range of 0° C. to 100°C., conveniently at ambient temperature.

Compounds of the generic structure 1 can also be obtained by treatingthe starting sulfonamide (Scheme II) with a base such as LDA, NaH,dimsyl salt, alkyl lithium, potassium carbonate, under an inertatmosphere such as argon or nitrogen, in a solvent such as benzene,toluene, DMF or THF with an alkylating group containing a leaving groupsuch a Cl, Br, I, MsO—, TsO—, TFAO—, represented by E in Scheme II. Apreferred solvent for this reaction is THF and the preferred base islithium bis(trimethylsilyl)amide. This reaction can be carried out at atemperature range of 0° C. to 100° C., conveniently at ambienttemperature.

Sulfonic esters (2) and sulfinic esters (4) may be prepared by reactingthe appropriate starting phenol in a solvent such as THF, DMF, tolueneor benzene in the presence of a base such as pyridine, triethylamine,sodium carbonate, potassium carbonate or 4-dimethylaminopyridine withpentafluorophenylsulfonyl chloride or pentafluorophenylsulfinylchloride, respectively. Pyridine itself may also be used as the solvent.Preferred solvents are pyridine and DMF and preferred bases are sodiumcarbonate and potassium carbonate. This reaction can be carried out at atemperature range of 0° C. to 100° C., conveniently at ambienttemperature.

Compounds of the general structure 5, in which Ar is an aromatic groupand x is from one to three, can be obtained from the correspondingmethyl ethers (Scheme III) by reaction with boron tribromide in asolvent of low polarity such as hexanes or CH₂Cl₂ under an inertatmosphere at a temperature ranging from −45° to 30° C. In a preferredembodiment, the reaction is carried out in CH₂Cl₂ at about 30° C.

Occasionally, the substrates for the transformations shown in SchemesI-III may contain functional groups (for example, amino, hydroxy orcarboxy) which are not immediately compatible with the conditions of thegiven reaction. In such cases, these groups may be protected with asuitable protective group, and this protective group removed subsequentto the transformation to give the original functionality using well knowprocedures such as those illustrated in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Second Edition, John Wiley &Sons, Inc., 1991.

The compounds used as initial starting materials in this invention maybe purchased from commercial sources or alternatively are readilysynthesized by standard procedures which are well know to those ofordinary skill in the art.

Some of the compounds of formula I may exist as stereoisomers, and theinvention includes all active stereoisomeric forms of these compounds.In the case of optically active isomers, such compounds may be obtainedfrom corresponding optically active precursors using the proceduresdescribed above or by resolving racemic mixtures. The resolution may becarried out using various techniques such as chromatography, repeatedrecrystallization of derived asymmetric salts, or derivatization, whichtechniques are well known to those of ordinary skill in the art.

The compounds of formula I which are acidic or basic in nature can forma wide variety of salts with various inorganic and organic bases oracids, respectively. These salts must be pharmacologically acceptablefor administration to mammals. Salts of the acidic compounds of thisinvention are readily prepared by treating the acid compound with anappropriate molar quantity of the chosen inorganic or organic base in anaqueous or suitable organic solvent and then evaporating the solvent toobtain the salt. Acid addition salts of the basic compounds of thisinvention can be obtained similarly by treatment with the desiredinorganic or organic acid and subsequent solvent evaporation andisolation.

The compounds of the invention may be labeled in a variety of ways. Forexample, the compounds may be provided as radioactive isotopes; forexample, tritium and the ¹⁴C-isotopes. Similarly, the compounds may beadvantageously joined, covalently or noncovalently, to a wide variety ofjoined compounds which may provide pro-drugs or function as carriers,labels, adjuvents, coactivators, stabilizers, etc. Hence, compoundshaving the requisite structural limitations encompass such compoundsjoined directly or indirectly (e.g. through a linker molecule), to suchjoined compounds.

A wide variety of indications may be treated, either prophylactically ortherapeutically, with the compounds and compositions of the presentinvention. For example, the subject compounds and compositions have beenfound to be effective modulators of cell proliferation. Limitation ofcell growth is effected by contacting a target cell, in or ex vivo, withan effective amount of one or more of the subject compositions orcompounds. Compounds may be assayed for their ability to modulatecellular proliferation using cell and animal models to evaluate cellgrowth inhibition and cytotoxicity, which models are known in the art,but are exemplified by the method of S. A. Ahmed et al. (1994) J.Immunol. Methods 170: 211-224, for determining the effects of compoundson cell growth.

Conditions amenable to treatment by the compounds and compositions ofthe present invention include any state of undesirable cell growth,including various neoplastic diseases, abnormal cellular proliferationsand metastatic diseases, where any of a wide variety of cell types maybe involved, including cancers such as Kaposi's sarcoma, Wilms tumor,lymphoma, leukemia, myeloma, melanoma, breast, ovarian, lung, etc, andothers such as cystic disease, cataracts, psoriasis, etc. Otherconditions include restenosis, where vascular smooth muscle cells areinvolved, inflammatory disease states, where endothelial cells,inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.trypanosomes, fungi, etc) are also subject to selective proliferativecontrol using the subject compositions and compounds.

Many of the subject compounds have been shown to bind to the β-subunitof tubulin and interfere with normal tubulin function. Hence, thecompounds provide agents for modulating cytoskeletal structure and/orfunction. Preferred compounds bind irreversibly or covalently, and henceprovide enhanced application over prior art microtubule disruptors suchas colchicine. The compositions may be advantageously combined and/orused in combination with other antiproliferative chemotherapeuticagents, different from the subject compounds (see Margolis et al. (1993)U.S. Pat. No. 5,262,409). Additional relevant literature includes: Wooet al. (1994) WO94/08041; Bouchard et al. (1996) WO96/13494; Bombardelliet al. (1996) WO96/11184; Bonura et al. (1992) WO92/15291.

Analysis

The subject compositions were demonstrated to have pharmacologicalactivity in in vitro and in vivo assays, e.g. are capable ofspecifically modulating a cellular physiology to reduce an associatedpathology or provide or enhance a prophylaxis. Preferred compoundsdisplay specific toxicity to various types of cells. Certain compoundsand compositions of the present invention exert their cytotoxic effectsby interacting with cellular tubulin. For certain preferred compoundsand compositions of the present invention, that interaction is covalentand irreversible. For example, exposure of a wide variety of tissue andcell samples, e.g. human breast carcinoma MCF7 cells, to tritiated formsof these preferred compounds, e.g. Compound 7 (Example 72), results inthe irreversible labeling of only one detectable cellular protein, whichwas found to be tubulin. This protein is a key component ofmicrotubules, which constitute the cytoskeleton and also play criticalroles in many other aspects of the cell's physiology, including celldivision. The labeling of tubulin by the subject preferred compounds isalso shown to be dose-dependent. The site of covalent binding on tubulinis identified as Cysteine-239 on the β-tubulin chain. The same Cys-239residue is selectively covalently modified when present in a widevariety of Cys-239 containing β-tubulin petides (e.g. Ser-234 toMet-267) provided in vitro or in vivo. One embodiment of these preferredcompounds provides the binding mechanism shown in Scheme IV, namely,displacement of the para-fluorine atom by the thiol group of Cys-239.Consistent with the ability of these compounds to bind to β-tubulin,treatment of a wide variety of cell and tissue types with variousconcentrations of the compounds resulted in widespread, irreversibledisruption of the cytoskeleton of most cells.

As discribed inter alia in Luduena (1993) Mol Biol of the Cell 4,445-457, tubulin defines a family of heterodimers of two polypeptides,designated α and β. Moreover, animals express multiple forms (isotypes)of each α and β polypeptides from multiple a and β genes. Many βisotypes comprise a conserved cysteine, Cys-239 (of human β2 tubulin:because of upstream sequence variations, the absolute position ofCys-239 is subject to variation, though Cys-239 is readily identified bythose in the art by its relative position (i.e. context withinencompassing consensus sequence, e.g. at least 8, preferably 12, morepreferably 16, most preferably 20 residue consensus peptide region ofthe isotype or fragment thereof, which region contains Cys-239). Byselective binding to Cys-239 is meant that Cys-239 is preferentiallybound relative to all other residues, including cysteins of the protein,by at least at least a factor of 2, preferably 10, more preferably 100,most preferably 1,000. In a particularly prefered embodiment, Cys-239 issubstantially exclusively and preferably exclusive bound. By selectivebinding to or modification of tubulin is meant that tubulin ispreferentially modified relative to all other proteins, by at least afactor of 2, preferably 10, more preferably 100, most preferably 1,000.In a particularly prefered embodiment, tubulin is substantiallyexclusively and preferably exclusive modified.

Compounds may be evaluated in vitro for their ability to inhibit cellgrowth, for example, as described in S. A. Ahmed et al. (1994) J.Immunol. Methods 170:211-224. In addition, established animal models toevaluate antiproliferative effects of compounds are known in the art.For example, several of the compounds disclosed herein are shown toinhibit the growth of human tumors, including MDR and taxol and/orvinblastine-restistant tumors, grafted into immunodeficient mice (usingmethodology similar to that reported by J. Rygaard and C. O. Povlsen(1969) Acta Pathol. Microbiol. Scand. 77:758-760, and reviewed by B. C.Giovanella and J. Fogh (1985) Adv. Cancer Res. 44:69-120.

Formulation and Administration

The invention provides methods of using the subject compounds andcompositions to treat disease or provide medicinal prophylaxis, to slowdown and/or reduce the growth of tumors, to treat bacterial infections,etc. These methods generally involve contacting cells with oradministering to the host an effective amount of the subject compoundsor pharmaceutically acceptable compositions.

The compositions and compounds of the invention and the pharmaceuticallyacceptable salts thereof can be administered in any effective way suchas via oral, parenteral or topical routes. Generally, the compounds areadministered in dosages ranging from about 2 mg up to about 2,000 mg perday, although variations will necessarily occur depending on the diseasetarget, the patient, and the route of administration. Preferred dosagesare administered orally in the range of about 0.05 mg/kg to about 20mg/kg, more preferably in the range of about 0.05 mg/kg to about 2mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mgper kg of body weight per day.

In one embodiment, the invention provides the subject compounds combinedwith a pharmaceutically acceptable excipient such as sterile saline orother medium, water, gelatin, an oil, etc. to form pharmaceuticallyacceptable compositions. The compositions and/or compounds may beadministered alone or in combination with any convenient carrier,diluent, etc. and such administration may be provided in single ormultiple dosages. Useful carriers include solid, semi-solid or liquidmedia including water and non-toxic organic solvents.

In another embodiment, the invention provides the subject compounds inthe form of a pro-drug, which can be metabolically converted to thesubject compound by the recipient host. A wide variety of pro-drugformulations are known in the art.

The compositions may be provided in any convenient form includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

The compositions may be advantageously combined and/or used incombination with other antiproliferative therapeutic or prophylacticagents, different from the subject compounds. In many instances,administration in conjunction with the subject compositions enhances theefficacy of such agents. Exemplary antiproliferative agents includecyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin,vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen,flutamide, hydroxyurea, and mixtures thereof.

The compounds and compositions also find use in a variety of in vitroand in vivo assays, including diagnostic assays. In certain assays andin in vivo distribution studies, it is desirable to used labeledversions of the subject compounds and compositions, e.g. radioliganddisplacement assays. Accordingly, the invention provides the subjectcompounds and compositions comprising a detectable label, which may bespectroscopic (e.g. fluorescent), radioactive, etc.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

¹H NMR spectra were recorded on a Varian Gemini 400 MHz NMRspectrometer. Significant peaks are tabulated in the order: multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), couplingconstant(s) in Hertz, number of protons. Electron Ionization (EI) massspectra were

recorded on a Hewlett Packard 5989A mass spectrometer. Fast AtomBombardment (FAB) mass spectroscopy was carried out in a VG analyticalZAB 2-SE high field mass spectrometer. Mass spectroscopy results arereported as the ratio of mass over charge, and the relative abundance ofthe ion is reported in parentheses.

Example 1

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene. ToN,N-dimethyl-1,4-phenylalanine dihydrochloride (3 g, 14.6 mmol)suspended in pyridine (50 mL) at 0° C. under argon was added dropwisepentafluorophenylsulfonyl chloride (2.38 mL, 16 mmol). The reactionmixture was stirred for 30 min at 0° C. and allowed to warm to ambienttemperature. The reaction mixture was stirred at room temperature for 3h. The volume of the mixture was then reduced to 10 mL under reducedpressure. The mixture was diluted with ethyl acetate and the reactionquenched with water. The layers were separated and the aqueous layerextracted twice with ethyl acetate. The organic layers were combined andwashed with brine and dried with MgSO₄. The solvent was evaporated andthe residue purified by chromatography on silica, eluting with CH₂Cl₂.The title product was obtained as a white solid in 63% yield (3.4 g). ¹HNMR (CDCl₃): 7.01(d, J=8.9 Hz, 2H), 6.77(s, 1H), 6.59(d, J=8.3 Hz, 2H),2.92 ppm (s, 6H). FAB m/z (relative abundance): 367(100%, M+H⁺),135(30%), 121(25%). Anal. calcd. for C₁₄H₁₁F₅N₂O₂S: C, 45.95; H, 3.03;N, 7.65. Found C, 45.83; H, 2.99; N, 7.62

Example 2

3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃): 7.12(t, J=8 Hz, 1H), 7.05(s, 1H), 6.57(s, 1H) 6.53(d, J=8 Hz,1H), 6.40(d, J=8 Hz, 1H), 2.94 ppm (s, 6H). FAB m/z: 366 (100%, M⁺). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-(N,N-dimethylamino)aniline.

Example 3

1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃):6.97(s, 1H), 6.76(d, J=8.6 Hz, 1H), 6.72(d, J=2.6 Hz, 1H), 6.62(dd,J=8.6, 2.6 Hz, 1H), 4.21 ppm (s, 4H). FAB m/z: 381(100%, M+H⁺). Analcalcd. for C₁₄H₈F₅NO₄S: C, 44.09; H, 2.12; N, 3.68; S, 8.39. Found: C,43.83; H, 2.19; N, 3.62; S, 8.20. The compound was prepared by aprotocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with3,4-ethylenedioxyaniline.

Example 4

1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃): 6.8 5(s, 1H), 6.78 (s, 1H), 6.70(d, J=8 Hz, 1H), 6.57(d, J=8Hz, 1H), 5.97 ppm(s, 2H). The compound was prepared by a protocolsimilar to that of example 1 by replacing N,N-dimethyl-1,4-phenyldiaminedihydrochloride with 3,4-methylenedioxyaniline.

Example 5

1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃):6.98(s, 1H), 6.85(d, 1H), 6.74(d, 1H), 6.60(dd, 1H), 3.85(s, 3H), 3.83ppm (s, 3H). EI, m/z: 383(50, M⁺), 152(100). The compound was preparedby a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with3,4-dimethoxyaniline.

Example 6

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃): 6.93(s, 1H), 6.7-6.8(m, 3H), 5.68(bs, 1H), 3.85 ppm(s, 3H). EI,m/z: 333(20, M⁺), 138(100). mp 118-120° C. The compound was prepared bya protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-hydroxy-4-methoxyaniline.

Example 7

2-Fluoro-1-methoxy-4-pentafluorosulfonamidobenzene. ¹H NMR (DMSO) 11.15(broad s, 1H), 7.13 (t, J=9 Hz, 1H), 7.02 (dd, J=9.5 2.5 Hz, 1H), 6.94ppm (dd, J=8.8 1.5 Hz, 1H), 3.79 ppm (s, 3H). EI, m/z: 371 (20, M⁺), 140(100). Anal. calcd. for C₁₃H₇HF₆N₁O₃S₁: C, 42.06; H, 1.90; N 3.77, S8.64. Found: C, 42.19; H, 1.83; N 3.70; S, 8.60. Mp 118-119° C. Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-fluoro-p-anisidine.

Example 8

4-Methoxy-1-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃): 6.99(s, 1H), 6.96(d, J=4 Hz, 2H), 6.88 (d, J=4 Hz, 2H), 3.83 ppm(s, 3H). EI,m/z: 353 (60, M⁺), 122 (100). M.p. 102-103° C. The compound was preparedby a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 4-methoxyaniline.

Example 9

3-Hydroxy-1-pentafluorophenylsulfonamidobenzene. ¹H NMR (CD₃OD): 7.15(t,J=8.1 Hz, 1H), 6.67(t, J=2.2 Hz, 1H) 6.60(dd, J=1.3 Hz, 7.8 Hz, 1H),6.52 ppm (dd, J=2.4 Hz 8.3 Hz, 1H). EI, m/z: 339 (80, M⁺), 256 (50), 81(100). The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3-hydroxyaniline.

Example 10

4-Hydroxy-1-pentafluorosulfonamidobenzene. ¹H NMR (CD₃OD): 6.95(d, J=8.9Hz, 2H), 6.65 ppm (d, J=8.9 Hz, 2H). EI, m/z: 339 (30, M⁺). The compoundwas prepared by a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 4-hydroxyaniline.

Example 11

1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃):7.03(d, J=7.9 Hz, 1H), 6.92(s, 1H), 6.85-6.82(m, 2H), 2.18(s, 3H), 2.16ppm(s, 3H). The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3,4-dimethylaniline.

Example 12

4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃): 6.93 (d, J=8.8 Hz, 2H), 6.78(s, 1), 6.45(d, J=8.7 Hz, 2H),3.25(dd, J=7.0 Hz, 7.3 Hz,4H), 1.10 ppm (t, J=7.2 Hz, 6H). The compoundwas prepared by a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with4-(N,N-diethylamino)aniline.

Example 13

4-Amino-1-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃): 6.82(d,J=8.7 Hz, 2H), 6.49 ppm(d, J=8.7 Hz, 2H). EI, m/z: 338(7, M⁺), 107(100),80(40). The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 1,4-diaminobenzene.

Example 14

Pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃): 7.30(d, J=8 Hz,2H), 7.13-7.2(m, 3H), 7.0 ppm(s, 1H). EI, m/z: 323(90, M⁺), 92(100). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with aniline.

Example 15

5-Pentafluorophenylsulfonamidoindazole. ¹H NMR (CD₃OD): 7.98(s, 1H),7.69(s, 1H), 7.47(d, J=8.3 Hz, 1H), 7.23 ppm(d, J=8.3 Hz, 1H). EI m/z:364(50, M+H⁺), 133(100). The compound was prepared by a protocol similarto that of example 1 by replacing N,N-dimethyl-1,4-phenyldiaminedihydrochloride with 5-aminoindazole.

Example 16

5-Pentafluorophenylsulfonamidoindole. ¹H NMR (CDCl₃): 8.2(s, 1H),7.43(s, 1H), 7.3(d, J=8 Hz, 1H), 7.22(s, 1H)), 6.98 (d, J=8 Hz, 1H),6.92 ppm (s, 1H), 6.50 ppm(s, 1H). EI m/z: 362(M⁺), 131(100). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with5-aminoindole.

Example 17

4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonanido)benzene.

4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg,0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system wasadded under N₂ at room temperature a 1 M solution of lithiumbis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirredfor 10 min followed by addition of MeI (65 mg, 0.028 mL). The reactionmixture was stirred overnight, the solvent was evaporated under reducedpressure and the crude product purified by HPLC using silica as thestationary phase and eluting with 20% EtOAc/Hex (v/v) to afford theproduct as a white solid in 60% yield (62 mg). EI m/z: 380(35, M⁺),149(100). ¹H NMR (CD₃OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H),3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C₁₅H₁₃F₅SO₂N₂: C, 47.37; H,3.45; N, 7.37. Found: C, 47.37; H, 3.49; N, 7.32.

Example 18

1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene.

1-Hydroxy-2-methoxy-4-pentafluorophenylsulfonamidobenzene (250 mg, 0.678mmol) was suspended in dry CH₂Cl₂ (5 mL) at 0° C. under nitrogen. To themixture was added BBr₃ as a 1M solution in CH₂Cl₂ (0.746 mmol, 1.1 eq.).The mixture was warmed to ambient temperature and stirred overnight. Thereaction mixture was poured over ice (75 mL) and extracted 3 times with30 mL portions of CH₂Cl₂. The organic layer was dried with MgSO₄, andthe solvent was evaporated. The crude product was purified bychromatography over silica eluting with 30% (v/v) EtOAc/Hex to affordthe product as a white solid in 41% yield (98 mg). ¹H NMR (DMSO):10.63(s, 1H), 9.15(s, 1H), 8.91(s, 1H), 6.61(d, J=9 Hz, 1H), 6.58(d, J=3Hz, 1H), 6.39 ppm(dd, J=9 Hz 3 Hz, 1H).

Example 19

4-Ethoxy-1-pentafluorophenylsulfonamidobenzene. To a stirred solution ofp-phenetidine (0.100 g, 0.729 mmol) in dimethylformamide (3.65 mL) at25° C. was added pentafluorophenyl sulfonyl chloride (0.135 mL, 0.91mmol), followed by sodium carbonate (0.116 g, 1.09 mmol), and thereaction mixture was stirred for 18 hours. The reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with 20% ammonium chloride(2×20 mL) and saturated sodium chloride (2×20 mL). The organic layer wasdried (sodium sulfite), and the ethyl acetate was removed under reducedpressure to yield a reddish-brown oil. Column chromatography (3:1 ethylacetate/hexane) yielded the title compound (0.222 g, 83%). ¹H NMR(CDCl₃) 7.08 (d, J=9 Hz, 2H), 7.04 (s, 1H), 6.80 (d, J=9 Hz, 2H), 3.96(q, J=7 Hz, 2H), 1.37 ppm (t, J=7 Hz, 2H). IR (neat) 3000-3600, 1750cm⁻¹. EI m/z : 367(M⁺), 154, 136.

The compounds of Examples 20 through 26 were prepared by a protocolsimilar to that of Example 19 by replacing p-phenetidine with theappropriate amine.

Example 20

3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3,5-dimethoxyaniline. ¹H NMR (CDCl₃) 6.91(s, 1H),6.32(s, 2H), 6.25(s, 1H), 3.72 ppm(s, 6H).

Example 21

3-Ethoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-ethoxyaniline. ¹H NMR (CDCl₃) 7.35 (t, J=8 Hz, 1H),7.21(s, 1H), 6.92( s, 1H), 6.86(d, J=8 Hz, 1H), 6.83(d, J=8 Hz, 1H),4.15( q, J=6 Hz, 2H), 1.56 ppm ( t, J=6 Hz, 3H).

Example 22

7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 2-amino-7-hydroxynaphthalene. ¹H NMR (CDCl₃) 8.15 (t,J=8 Hz, 1H), 7.55( d, J=8 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=8 Hz, 1H),7.40 (s, 1H), 6.88 ppm (q, J=8 Hz, 1H).

Example 23

3-Phenoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-phenoxyaniline. ¹H NMR (CDCl₃) 7.34 ( t, J=8 Hz,2H), 7.26 ( t, J=8 Hz, 1H), 7.16 ( t, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 2H),6.86 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.74 (s, 1H).

Example 24

3-Methoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-methoxyaniline. ¹H NMR (CDCl₃) 7.20 (d, J=8 Hz, 1H,), 6.95 (s, 1H), 6.78 (d, J=8 Hz, 1H,), 6.70 (t, J=8 Hz, 1H), 3.79 ppm(s, 1H).

Example 25

4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 4-(1-morpholino)aniline. ¹H NMR (CDCl₃) 7.09 (d, J=8Hz, 2H), 6.85 (d, J=8 Hz, 2H), 3.85 (t, J=8 Hz, 4H), 3.15 ppm (t, J=8Hz, 4H).

Example 26

5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3,4,5-trimethoxyaniline. ¹H NMR (CDCl₃) 8.14 (s, 1H),6.46 (s, 2H), 3.69 (s, 6H), 3.59 (s, 3H).

Example 27

1,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene.

1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene.

5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene.

1,2,3-Methoxy-5-pentafluorophenylsulfonamidobenzene (269 mg, 0.65 mmol)was suspended in dry CH₂Cl₂ (5 mL) at 0° C. under nitrogen. To themixture was added BBr₃ as a 1M solution in CH₂Cl₂ (3.26 mmol, 5 eq.).The mixture was warmed to ambient temperature and stirred overnight. Thereaction mixture was poured over ice (75 mL) and extracted 3 times with30 mL portions of CH₂Cl₂. The organic layer was dried with MgSO₄,evaporated, and the residue was subjected to chromatography over silicaeluting with 30% (v/v) EtOAc/Hex to afford the three products. Thecompounds of Examples 28 and 29 were prepared in a manner similar tothat described above beginning with the product of Example 20 andtreating it with BBr₃.

1,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃) 10.85 (s, 1H), 8.31 (s, 1H), 6.41 (s, 2H), 3.66 ppm (s, 6H).

1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃) 10.73 (s, 1H), 8.31 (s, 1H), 6.27 (s, 1H), 6.26 (s, 1H), 3.66ppm (s, 3H).

5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene. ¹H NMR (CDCl₃)11.0 (s, 1H), 9.03 (s, 2H), 8.06 (s, 1H), 6.13 ppm (s, 2H).

Example 28

3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃) 11.2 (s, 1H), 9.63 (s, 1H), 6.23 (s, 1H), 6.21 (s, 1H), 6.08 (s,1H), 3.63 (s, 3H).

Example 29

3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃) 7.15(s, 1H), 6.25 (s, 2H), 6.15 (s, 1H), 5.31 (s, 2H).

Example 30

2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene.Prepared using a procedure similar to that of Example 18 replacing4-(N,N-dimethylamino)-1-pentafluorophenylsulfonamidobenzene with theappropriate non-substituted sulfonamide (product of Example 7). ¹H NMR(CDCl₃): 6.97-6.94(m, 2H), 6.89(t, J=9 Hz, 1H), 3.87(s, 3H), 3.35ppm (t,J=1 Hz). EI m/z: 385(20, M⁺), 154(100). Anal. calcd. for C₁₄H₉F₆NO₃: C,43.64; H,2.35; N, 3.64. Found C, 43.55; H, 2.38; N, 3.65.

Example 31

2-Bromo-1-methoxy4-pentafluorophenylsulfonamidobenzene. ¹H NMR (CDCl₃):7.35(d, J=3 Hz, 1H), 7.15(dd, J=9 Hz, 3 Hz, 1H), 6.97 (s, 1H), 6.81(d,J=9 Hz, 1H), 3.88 ppm (s, 3H). EI m/z: 433(35, M⁺), 202(100). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-bromo-4-methoxyaniline.

Example 32

2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene. ¹H NMR(CDCl₃): 7.19(d, J=3 Hz, 1H), 7.08(dd, J=9 Hz, 3 Hz, 1H), 7.01 (s, 1H),6.84(d, J=9 Hz, 1H), 3.85 ppm (s, 3H). EI m/z (rel. abundance): 387(10,M⁺), 156(100). The compound was prepared by a protocol similar to thatof example 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3-chloro-4-methoxyaniline.

Example 33

4-(N,N)-Dimethylamino)-1-pentafluorophenylsulfonamidobenzenehydrochloride.

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene (2 g, 5.5mmol) was dissolved in 15 mL of diethyl ether at ambient temperatureunder nitrogen. Gaseous HCl was bubbled into the reaction mixture for 5min. The mixture was filtered and the resulting solid washed twice with15 mL portions of ice cold diethyl ether to afford the product as awhite solid (1.89 g, 86% yield). ¹H NMR (CD₃OD): 7.62(dd, J=9.0 Hz, 1.6Hz, 2H), 7.44(dd, J=9.0 Hz, 1.6 Hz, 2H), 3.28 ppm (s, 6H). FAB m/z:367(100%, M+H⁺), 135(90%), 121(45%). Anal. calcd. for C₁₄H₁₃ClF₅N₂O₂S:C, 41.79; H, 3.01; N, 6.97; S, 7.95. Found C, 41.71; H, 3.05; N, 7.01;S, 7.96.

Example 34

3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-difluoroaniline.¹H NMR (CDCl₃) 7.13 (m, 3H), 6.91 ppm (m, 1H). EI, m/z (relativeabundance): 359 (20), 128 (100). Anal. calcd. for C₁₃H₄F₇NO₂S: C, 40.12;H, 1.12; N, 3.90. Found: C, 40.23; H, 1.17; N, 3.89.

Example 35

4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with4-(trifluoromethoxy)aniline. ¹H NMR (CDCl₃) 7.18 ppm (m, 4H). EI, m/z(relative abundance): 407 (20), 176 (100). Anal. calcd. for C₁₃H₅F₈NO₃S:C, 38.34; H, 1.24; N, 3.44. Found: C, 38.33; H, 1.30; N, 3.43.

Example 36

2-Chloro-5-pentafluorophenylsulfonamidopyridine. The compound wasprepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with5-amino-2-chloropyridine. H NMR (DMSO-d⁶): 8.18 (d, J=2.68 Hz, 1H), 7.64(dd, J=8.75, 2.89 Hz, 1H), 7.50 ppm (d, J=8.75 Hz, 1H). EI m/z 358 (20,M⁺), 127 (100). Anal. calcd. for C₁₁H₄ClF₅N₂O₂S: C, 36.83; H, 1.12; N,7.81; S, 8.94; Cl, 9.90. Found: C, 37.00; H, 1.16; N, 7.78; S, 8.98; Cl,10.01. White crystals with M.P.=144-145° C.

Example 37

2-Hydroxy-1-methoxy-4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzene.

N-(5-hydroxypentyl)-2-hydroxy-1-methoxy-4-aminobenzene was prepared byreductive amination of 5-amino-2-methoxy phenol with glutaric dialdehydewith NaBH₄ in MeOH.2-Hydroxy-1-methoxy-4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzenewas prepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride withN-(5-hydroxypentyl)-2-hydroxy-1-methoxy-4-aminobenzene. ¹H NMR (CDCl₃):6.78(d, J=8.6 Hz, 1H), 6.71(dd, J=8.59, 2.48 Hz, 1H), 6.63(d, J=2.48 Hz,1H), 3.88(s, 3H), 3.7(t, J=6.8 Hz, 2H), 3.6(t, J=6.39 Hz, 2H), 1.5 ppm(m, 6H). Anal. calcd. for C₁₈H₁₈F₅NO₅S: C, 47.47; H, 3.98; N, 3.08; S,7.04. Found: C, 47.47; H, 4.04; N, 3.11; S, 6.97. White crystals withM.P.=118°.

Example 38

4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene.

The compound was prepared in a manner similar to example 46 by replacing3-chloroaniline with 4-t-butoxyaniline. 4-t-Butoxyaniline was preparedby the method of Day (J. Med. Chem. 1975, 18, 1065). ¹H NMR (CDCl₃): d7.07 (m, 2), 6.92 (m, 2), 6.88 (m, 1), 1.31 (s, 9). MS (EI): m/z 395 (1,M⁺), 339 (28), 108 (100). Anal. Calcd. for C₁₆H₁₄F₅NO₃S: C, 48.61; H,3.57; N, 3.54; S, 8.11. Found: C, 48.53; H, 3.60; N, 3.50; S, 8.02.

Example 39

1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 6 withN-bromosuccinimide in dichloromethane. ¹H NMR (CDCl₃) 7.28(br s, 1H),7.21 (d, J=9 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 6.05 (s, 1H), 3.89 ppm (s,3H). EI, m/z (relative abundance) : 449 (25), 447 (25), 218 (100), 216(100). Anal. calcd. for C₁₃H₈BrF₅NO₄S: C, 34.84; H, 1.57; N, 3.13; S,7.15. Found: C, 34.75; H, 1.60; N, 3.07; S, 7.08.

Example 40

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 6 withN-bromosuccinimide in dichloromethane. ¹H NMR (CDCl₃) 7.28 (s, 1H), 7.16(br s, 1H), 6.91 (s, 1H), 5.63 (s, 1H), 3.85 ppm (s, 3H). EI, m/z(relative abundance) : 449 (25), 447 (25), 218 (100), 216 (100). Anal.calcd. for C₁₃H₈BrF₅NO₄S: C, 34.84; H, 1.57; N, 3.13; S, 7.15. Found: C,34.84; H, 1.57; N, 3.05; S, 7.06.

Example 41

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 7 withbromine water. 1H NMR (CDCl₃): 7.49 (d, J=11.72 Hz, 1H), 7.21 (s, 1H),7.04 (d, J=8.2 Hz, 1H), 3.84 ppm (s, 3H). EI m/z: 449 (20, M⁺), 451(20), 228 (100), 230 (100). Anal. Calcd. for C₁₃H₆BrF₆NO₃S: C, 34.69; H,1.34; N, 3.11; S, 7.12; Br, 17.75. Found: C, 34.76; H, 1.29; N, 3.05; S,7.12; Br, 17.68. White crystals with M.P.=109° C.

Example 42

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene sodium salt.The compound was prepared by treating the compound of example 6 with anequimolar amount of 1N NaOH_((aq)). The mixture was then lyophilized andthe residue recrystallyzed from ethyl acetate/ ether. ¹H NMR (DMSO) 8.40(s, 1H), 6.57 (d, J=9 Hz, 1H), 6.39 (d, J=2 Hz, 1H), 6.24 (dd, J=9, 2Hz, 1H), 3.62 ppm (s, 3H). Anal. calcd. for C ₃H₇F₅NNaO₄S: C, 39.91; H,1.80; N, 3.58; Na, 5.88; S, 8.19. Found: C, 39.79; H, 1.86; N, 3.50; Na,5.78; S, 8.07.

Example 43

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene potassiumsalt. The compound was prepared in a manner similar to that of example42 by replacing 1N NaOH with 1N KOH. ¹H NMR (DMSO) 8.30 (br s, 1H), 6.55(d, J=9 Hz, 1H), 6.36 (d, J=2 Hz, 1H), 6.25 (dd, J=9, 2 Hz, 1H), 3.61ppm (s, 3H). Anal. calcd. for C₁₃H₇F₅KNO₄S: C, 38.33; H, 1.73; N, 3.44;S, 7.87. Found: C, 38.09; H, 1.79; N, 3.39; S, 7.97.

Example 44

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene potassium salt.The compound was prepared in a manner similar to that of example 43 byreplacing the compound from example 6 with example 7. ¹H NMR (DMSO) 6.80(t, J=10 Hz, 1H), 6.72 (dd, J=9, 2 Hz, 1H), 6.54 (dd, J=9, 2 Hz, 1H),3.68 ppm (s, 3H). Anal. calcd. for C₁₃H₆F₆KNO₃S: C, 38.15; H, 1.48; N,3.42; S, 7.83. Found: C, 38.09; H, 1.51; N, 3.35; S, 7.73. M.P.=202-205°C.

Example 45

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene sodium salt.The compound was prepared in a manner similar to that of example 44 byreplacing 1N KOH with 1N NaOH. ¹H NMR (DMSO) 6.80 (t, J=10 Hz, 1H), 6.71(dd, J=9, 2 Hz, 1H), 6.53 (dd, J=9, 2 Hz, 1H), 3.69 ppm (s, 3H). Anal.calcd. for C₁₃H₆F₆NNaO₃S: C, 39.71; H, 1.54; N, 3.56; Na, 5.85; S, 8.15.Found: C, 39.56; H, 1.62; N, 3.49; Na, 5.88; S, 8.08. M.P.>250° C.

Example 46

3-Chloro-1-pentafluorophenylsulfonamidobenzene. To a solution ofpentafluorophenylsulfonyl chloride (0.15 mL, 1.00 mmol) in MeOH (4 mL)was added 3-chloroaniline (260 mg, 2.04 mmol). After stirring at rt for1 h, the reaction mixture was concentrated under reduced pressure andthe residue was taken up in EtOAc and then filtered through a plug ofsilica gel. The filtrate was concentrated to give a yellow oil that uponchromatography provided 265 mg (74%) of product. ¹H NMR (CDCl₃): d7.28-7.24 (m, 1H), 7.21-7.17 (m, 2H), 7.10-7.08 (m, 1H), 7.07 (s, 1H).MS (EI): m/z 357 (42, M⁺), 258 (76), 126 (87), 99 (100). Anal. Calcd.for C₁₂H₅ClF₅NO₂S: C, 40.30; H, 1.41; N, 3.92; S, 8.96. Found: C, 40.18;H, 1.35; N, 3.84; S, 8.90.

Example 47

4-Chloro-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 46 byreplacing 3-chloroaniline with 4-chloroaniline. ¹H NMR (CDCl₃): d 7.30(m, 2H), 7.20 (m, 1H), 7.14 (m, 2H). MS (EI): m/z 357 (27, M⁺), 258(38), 126 (100), 99 (85). Anal. Calcd. for C₁₂H₅ClF₅NO₂S: C, 40.30; H,1.41; N, 3.92; S, 8.96. Found: C, 40.19; H, 1.37; N, 3.87; S, 8.88.

Example 48

3-Nitro-1-pentafluorophenylsulfonamidobenzene. The compound was preparedin a manner similar to that described in example 46 by replacing3-chloroaniline with 3-nitroaniline. 1H NMR (CDCl₃): d 8.14 (s, 1H),8.06-8.03 (m, 2H), 7.66-7.63 (m, 1H), 7.55 (m, 1H). MS (EI): m/z 368(54, M⁺), 137 (70), 91 (100). Anal. Calcd. for C₁₂H₅F₅N₂O₄S: C, 39.14;H, 1.37; N, 7.61; S, 8.71. Found: C, 39.39; H, 1.45; N, 7.46; S, 8.58.

Example 49

4-Methoxy-1-pentafluorophenylsulfonamido-3-trifluoromethylbenzene. Thecompound was prepared in a manner similar to that described in example46 by replacing 3-chloroaniline with 4-methoxy-3-trifluoromethylanilinewhich was obtained by the hydrogenation of the corresponding nitrocompound. White solid, mp 121-123° C. ¹H NMR (CDCl₃): d 7.43-7.37 (m,2H), 6.96 (d, J=8.8, 1H), 3.88 (s, 3H). MS (EI): m/z 421 (16, M⁺), 190(100). Anal. Calcd. for C₁₄H₇F₈NO₃S: C, 39.92; H, 1.67; N, 3.32; S,7.61. Found: C, 40.17; H, 1.68; N, 3.28; S, 7.67.

Example 50

4-Methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene. To asolution of 4-methoxy-1-pentafluorophenylsulfonamidobenzene (448 mg,1.27 mmol) in THF (3 mL) was added triphenylphosphine (333 mg, 1.27mmol) and allyl alcohol (0.09 mL, 1.27 mmol). Diethylazodicarboxylate(0.20 mL, 1.27 mmol) was added and the mixture was stirred at rt. After1 h, the reaction mixture was poured onto saturated NaCl (10 mL) andextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts werewashed with saturated NaHCO₃ (10 mL) and dried (MgSO₄). Concentrationfollowed by flash chromatography (25:25:1/hexanes:CH₂Cl₂:EtOAc) provided451 mg (90%) of product as a white solid, mp 59-60° C. ¹H NMR (CDCl₃): d7.06 (m, 2H), 6.85 (m, 2H), 5.79 (m, 1H), 5.15 (s, 1H), 5.11 (m, 1H),4.37 (d, J=6.3, 2H), 3.80 (s, 3H). MS (El): m/z 393 (33, M⁺), 162 (100),134 (66). Anal. Calcd. for C₁₆H₁₁F₅NO₃S: C, 48.98; H, 2.83; N, 3.57; S,8.17. Found: C, 49.13; H, 3.15; N, 3.63; S, 8.15.

Example 51

1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. Thecompound was prepared in a manner similar to that described in example50 by replacing allyl alcohol with 3-buten-1-ol. White solid, mp 64-66°C. ¹H NMR (CDCl₃): d 7.08 (m, 2H), 6.86 (m, 2H), 5.74 (m, 1H), 5.10-5.04(m, 2H), 3.83 (m, 2H), 3.81 (s, 3H), 2.25 (q, J=6.9, 2H). MS (EI): m/z407 (13, M⁺), 366 (24), 135 (100). Anal. Calcd. for C₁₇H₁₄F₅NO₃S: C,50.13; H, 3.46; N, 3.44; S, 7.87. Found: C, 50.25; H, 3.51; N, 3.43; S,7.81.

Example 52

4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Thecompound was prepared in a manner similar to that described in example50 by replacing allyl alcohol with 4-penten-1-ol. Low meltingsemi-solid. ¹H NMR (CDCl₃): d 7.08 (m, 2H), 6.87 (m, 2H), 5.74 (m, 1H),5.02-4.96 (m, 2H), 3.81 (s, 3H), 3.76 (t, J=7.04, 2H), 2.11 (q, J=6.9,2H), 1.60 (pentet, J=7.3, 2H). MS (EI): m/z 421 (30, M⁺), 190 (100).Anal. Calcd. for C₁₈H₁₆F₅NO₃S: C, 51.31; H, 3.83; N, 3.32; S, 7.61.Found: C, 51.44; H, 3.89; N, 3.38; S, 7.54.

Example 53

1-(N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido)-4-methoxybenzene.To a solution of4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene (101 mg,0.26 mmol) in acetone:water (8:1, 1 mL) at rt was addedN-methylmorpholine N-oxide (34.0 mg, 0.29 mmol) and OsO₄ (0.10 mL of0.16 M solution in H₂O, 1.60×10⁻² mmol). After stirring at rt for 18 h,the reaction mixture was treated with saturated NaHSO₃ (5 mL) andallowed to stir at rt. After 1 h, the reaction mixture was poured ontosaturated NaHSO₃ (5 mL) and extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated. Flashchromatography (1:1, 1:2/hexanes:EtOAc) afforded 90 mg (83%) of productas a white solid, mp 130-131° C. ¹H NMR (CDCl₃): d 7.11 (m, 2H), 6.85(m, 2H), 3.78 (s, 3H), 3.90-3.65 (m, 5H). Anal. Calcd. for C₁₆H₁₃F₅NO₅S:C, 45.08; H, 3.07; N, 3.29; S, 7.52. Found: C, 45.09; H, 3.33; N, 3.27;S, 7.46.

Example 54

1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene.The compound was prepared in a manner similar to that described inexample 53 by replacing4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene with1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. Whitesolid, mp 126-128° C. ¹H NMR (CDCl₃): d 7.10 (m, 2H), 6.88 (m, 2H), 4.13(m, 1H), 3.96 (m, 1H), 3.81 (s, 3H), 3.78-3.73 (m, 1H), 3.64 (dd, 1,J=2.9, 10.7, 1H), 3.47 (dd, J=7.3, 11.2; 1H), 2.67 (bs, 1H), 1.92 (bs,1H), 1.62 (m, 2H).

Example 55

1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene.The compound was prepared in a manner similar to that described inexample 53 by replacing4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene with4-methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Whitesolid, mp 116-118° C. ¹H NMR (CDCl₃): d 7.07 (m, 2H), 6.86 (m, 2H), 3.80(s, 3H), 3.78 (m, 2H), 3.71-3.62 (m, 2H), 3.43 (dd, J=7.5, 10.8; 1H),1.90 (bs, 2H), 1.66-1.49 (m, 4H). Anal. Calcd. for C₁₈H₁₈F₅NO₅S: C,47.48; H, 3.98; N, 3.08; S, 7.04. Found: C, 47.58; H, 3.95; N, 3.06; S,6.95.

Example 56

1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene. Toa solution of1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg,1.01 mmol) in THF (6.5 mL) at −78° C. was added BH₃.THF (1.00 mL of a 1M solution in THF, 1.00 mmol). After stirring at −78° C. for 1 h and at0° C. for 1 h, the reaction mixture was treated with H₂O (20 mL) andsodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, themixture was poured onto H₂O (20 mL) and extracted with CH₂Cl₂ (3×15 mL).The combined organic extracts were washed with sat. NaCl (20 mL) anddried (MgSO₄). Concentration followed by chromatography(2:1/hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid,mp 88-90° C. ¹H NMR (CDCl₃): d 7.08 (m, 2H), 6.85 (m, 2H), 3.80 (s, 3H),3.77 (m, 2H), 3.64 (t, J=6.0; 2H), 1.63-1.55 (m, 5H), 1.50 (bs, 1H).Anal. Calcd. for C₁₇H₁₆F₅NO₄S: C, 48.00; H, 3.79; N, 3.29; S, 7.54.Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.

Example 57

4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)benzene.The compound was prepared in a manner similar to that described inexample 56 by replacing1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene with4-methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Whitesolid, mp 96-97° C. ¹H NMR (CDCl₃): d 7.08 (m, 2H), 6.86 (m, 2H), 3.81(s, 3H), 3.76 (t, J=6.8, 2H), 3.62 (t, J=6.4; 2H), 1.58-1.43 (m, 6H).Anal. Calcd. for C₁₈H₁₈F₅NO₄S: C, 49.20; H, 4.13; N, 3.19; S, 7.30.Found: C, 49.11; H, 4.09; N, 3.14; S, 7.19.

Example 58

4-Methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to example 46 by replacing3-chloroaniline with 4-methoxy-3-nitroaniline which was prepared by themethod of Norris (Aust. J. Chem. 1971, 24, 1449). Orange-yellow solid,mp 95-97° C. ¹H NMR (CDCl₃): d 7.64 (d, J=2.7; 1H), 7.51 (dd, J=2.7,9.0; 1H), 7.09 (s, 1H), 7.09 (d, J=9.0; 1H), 3.95 (s, 3H). Anal. Calcd.For C₁₃H₇F₅N₂O₅S: C, 39.21; H, 1.77; N, 7.03; S, 8.05. Found: C, 39.19;H, 1.73; N, 6.97; S, 7.95.

Example 59

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene. To a solutionof 4-methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene (627 mg, 1.58mmol) in ethanol (10 mL) was added 10% Pd/C (51 mg). The resultingmixture was stirred under an atmosphere of hydrogen gas at 1 atmpressure. After 14 h, the mixture was passed through a pad of celite andthe filtrate was concentrated to give a solid residue. Silica gelchromatography (2:1, 1:1/hexanes:EtOAc) yielded 542 mg (93%) of productas a white solid, mp 142-143° C. ¹H NMR (DMSO-d₆): 10.64 (s, 1), 6.68(d, J=8.4; 1H), 6.44 (d, J=2.1; 1H), 6.30 (d, J=2.1, 8.4; 1H), 4.88 (bs,2H), 3.69 (s, 3H). Anal. Calcd. for C₁₃H₉F₅N₂O₃S: C, 42.40; H, 2.46; N,7.61; S, 8.71. Found: C, 42.29; H, 2.36; N, 7.52; S, 8.60.

Example 60

4-Butoxy-1-pentafluorophenylsulfonamidobenzene. To a solution ofpentafluorophenylsulfonyl chloride (203 mg, 0.763 mmol) in MeOH (4 mL)was added 4-butoxyaniline (0.26 mL, 1.53 mmol). After stirring at rt for1 h, the reaction mixture was poured onto 1 MHCl (15 mL) and extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were washed withsaturated NaCl (10 mL) and dried (MgSO₄). Concentration followed byflash chromatography (25:25:1/hexanes: CH₂Cl₂:EtOAc) provided 189 mg(63%) of product. ¹H NMR (CDCl₃): d 7.07 (m, 2H), 6.86 (s, 1H), 6.80 (m,2H), 3.89 (t, J=6.5; 2H), 1.73 (m, 2H), 1.46 (m, 2H), 0.95 (t, J=7.5;2H). MS (EI): m/z 395 (30, M⁺), 164 (35), 108 (100). Anal. Calcd. forC₁₆H₁₄F₅NO₃S: C, 48.61; H, 3.57; N, 3.54; S, 8.11. Found: C, 48.54; H,3.53; N, 3.50; S, 8.02.

Example 61

1-Pentafluorophenylsulfonamido-4-phenoxybenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-phenoxyaniline. ¹H NMR (CDCl₃):7.36-7.30 (m, 2H), 7.15-7.10 (m, 3H), 6.99 (s, 1H), 6.98-6.90 (m, 4H).MS (EI): m/z 415 (32, M⁺), 184 (100), 77 (66). Anal. Calcd. forC₁₈H₁₀F₅NO₃S: C, 52.05; H, 2.43; N, 3.27; S, 7.72. Found: C, 51.78; H,2.45; N, 3.25; S, 7.53.

Example 62

4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-benzyloxyaniline. 4-Benzyloxyanilinewas obtained from the commercially available hydrochloride salt bytreatment with aqueous NaOH. ¹H NMR (CDCl₃): 7.38-7.37 (m, 4H),7.36-7.32 (m, 1H), 7.10-7.08 (m, 2H), 7.91-7.88 (m, 2H), 6.78 (s, 1H),5.01 (s, 1H). MS (EI): m/z 429 (19, M), 91 (100). Anal. Calcd. forC₁₉H₁₂F₅NO₃S: C, 53.14; H, 2.82; N, 3.26; S, 7.45. Found: C, 53.07; H,2.78; N, 3.21; S, 7.35.

Example 63

4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-(methylmercapto)aniline. ¹H NMR(CDCl₃): 7.17 (m, 2H), 7.09 (m, 2H), 6.89 (m, 1H), 2.44 (s, 3H). MS(EI): m/z 369 (24, M⁺), 138 (100), 77 (66). Anal. Calcd. forC₁₃H₈F₅NO₂S₂: C, 42.28; H, 2.18; N, 3.79; S, 17.36. Found: C, 42.20; H,2.21; N, 3.72; S, 17.28.

Example 64

2-Methoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with o-anisidine. ¹H NMR (CDCl₃): d 7.54 (dd,J=1.5, 8.0; 1H), 7.13 (dt, J=1.5, 8.0; 1H), 6.94 (dt, J=1.2, 8.0; 1H),6.84 (dd, J=1.2, 8.0; 1H), 3.79 (s, 3H). MS (EI): m/z 353 (82, M⁺), 122(100), 94 (95). Anal. Calcd. for C₁₃H₈F₅NO₃S: C, 44.19; H, 2.28; N,3.97; S, 9.06. Found: C, 44.10; H, 2.26; N, 3.92; S, 9.03.

Example 65

4-Allyloxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in manner similar to that described in example 60 by replacing4-butoxyaniline with 4-allyloxyaniline. 4-Allyloxyaniline was preparedby the method of Butera (J. Med. Chem. 1991, 34, 3212). ¹H NMR (CDCl₃):7.08 (m, 2H), 6.87 (m, 1H), 6.82 (m, 2H), 6.04-5.94 (m, 1H), 5.39-5.34(m, 1H), 5.29-5.25 (m, 1H), 4.48-4.46 (m, 2H). MS (EI): m/z 379 (11,M⁺), 148 (32), 41 (100). Anal. Calcd. for C₁₅H₁₀F₅NO₃S: C, 47.50; H,2.66; N, 3.96; S, 8.45. Found: C, 47.53; H, 2.68; N, 3.62; S, 8.37.

Example 66

1-Pentafluorophenylsulfonamido-4-propoxybenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-propoxyaniline. 4-Propoxyaniline wasobtained by catalytic hydrogenation of 4-allyloxynitrobenzene.4-Allyloxynitrobenzene was prepared by the method of Butera (J. Med.Chem. 1991, 34, 3212). ¹H NMR (CDCl₃): 7.09 (m, 2H), 6.82 (m, 2H), 6.78(m, 1H), 3.87 (t, J=6.5; 2H), 1.78 (m, 2H), 1.02 (t, J=7.4; 3H). MS(EI): m/z 381 (20, M⁺), 150 (40), 108 (100). Anal. Calcd. forC₁₅H₁₂F₅NO₃S: C, 47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.01; H,3.20; N, 3.61; S, 8.31.

Example 67

4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-isopropoxyaniline. 4-Isopropoxyanilinewas prepared from 4-fluoronitrobenzene in analogy to the method of Day(J. Med. Chem. 1975, 18, 1065). ¹H NMR (CDCl₃): 7.08 (m, 2H), 7.00 (s,1H), 6.81 (m, 2H), 4.48 (heptet, J=6.1; 1H), 1.30 (d, J=6.04; 6H). MS(EI): m/z 381(7, M⁺), 339 (8), 108 (100). Anal. Calcd. for C₁₅H₁₂F₅NO₃S:C, 47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.08; H, 3.18; N, 3.60;S, 8.34.

Example 68

1-Pentafluorophenylsulfonyloxybenzene. To a stirred solution of phenol(0.068 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25° C. is addedpentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol), followed bysodium carbonate (0.116 g, 1.09 mmol), and the reaction mixture isstirred for 18 hours. The reaction mixture is diluted with ethyl acetate(50 mL), washed with 20% ammonium chloride (2×20 mL), and saturatedsodium chloride (2×20 mL). The organic layer is dried (sodium sulfite),and the ethyl acetate removed under vacuum. Column chromatography (3/1ethyl acetate/hexane) yields the title compound.

Example 69

1-Pentafluorophenylsulfonylindole. To a stirred solution of indole(0.085 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25° C. is addedpentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol), followed bysodium carbonate (0.116 g, 1.09 mmol), and the reaction mixture isstirred for 18 hours. The reaction mixture is diluted with ethyl acetate(50 mL), washed with 20% ammonium chloride (2×20 mL), and saturatedsodium chloride (2×20 mL). The organic layer is dried (sodium sulfite),and the ethyl acetate removed under vacuum. Column chromatography (3/1ethyl acetate/hexane) yields the title compound.

Example 70

2-Fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene. To3-fluoro-p-anisidine (3 g, 21.2 mmol) suspended in THF (50 mL) withpyridine (1.84 g, 23.3 mmol) at 0° C. under argon is added dropwisepentafluorophenylsulfinyl chloride (5.3 g, 21.2 mmol). The reactionmixture is stirred for 30 min. at 0° C. and allowed to warm to ambienttemperature. The reaction mixture is strirred at room temperature andfollowed by TLC. After the reaction is completed the mixture is dilutedwith ethyl acetate and the reaction quenched with water. The layers areseparated and the aqueous layer extracted twice with ethyl acetate. Theorganic layers are combined and dried with brine and with Na₂SO₄. Thesolvent is evaporated and the residue purified by chromatography onsilica to give the title compound.

Example 71

2-Anilino-3-pentafluorophenylsulfonamidopyridine. To a solution ofpentafluorophenylsulfonyl chloride (863 mg, 3.24 mmol) in pyridine (9mL) at rt was added 3-amino-2-analinopyridine (600 mg, 3.24 mmol). Afterstirring at rt overnight the reaction mixture was concentrated atreduced pressure and the residue partitioned between 1 M Hcl (50 mL) andCH2Cl2 (50 mL). The organic extract was dried and concentrated to givean oil which was purified by MPLC to give 377 mg (28%) of product as anorange solid. H¹ NMR (CDCl₃): 8.50 (bs, 1H), 7.80 (d, J=5.1, 1H), 7.61(d, J=8.0, 1H), 7.32 (t, J=8.0, 2H), 7.25 (d, J=8.0, 2H), 7.11 (t,J=7.3, 1H), 6.80 (dd, J=5.6, 7.7, 1H), 4.20 (bs, 1H). MS (FAB): m/z 438(M+Na), 416 (M+H).

Example 72

4-[3H]-1-Fluoro-2-methoxy-5-pentafluorosulfonamidobenzene.

A solution of1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene (27.8mg, 0.058 mmol; prepared in Example 41) in ethyl acetate (2 mL) wastreated with 100 mg of 10% palladium on charcoal. The air in thereaction vessel was evacuated and replaced with tritium gas. After 2 hof stirring at room temperature, the catalyst was filtered, the solventwas evaporated, and the crude product purified by preparative thin layerchromatography (TLC) using dichloromethane as the eluent. The samplepurity was characterized by HPLC using a Microsorb silica (250×4.6 mm) 5mm column and 15% ethyl acetate/hexane as the mobile phase. The elutionof material was detected using a UV detector at 254 nm and a Beta Ramdetector. The chemical purity of this material was determined to be100%, and the radiochemical purity was 99.3%. The specific activity ofthis material was Ci/mmol.

Example 73

Compounds were evaluated for their ability to inhibit in vitro thegrowth of HeLa cells, an immortal cell line derived from a humancervical carcinoma commonly used to evaluate the cytotoxicity ofpotential therapeutic agents. The following data reflect thecytotoxicity of selected examples of the present invention. The valuesgiven represent the concentration of test compound required to inhibitby 50% the uptake of Alamar Blue (Biosource International, Camarillo,Calif.) by HeLa cell cultures, which correlates directly with theoverall levels of cellular metabolism in the culture, and is generallyaccepted as an appropriate marker of cell growth. The test was conductedaccording to the method of S. A. Ahmed et al. (1994) J. Immunol. Methods170: 211-224. The following selected examples display potent cytotoxicactivity in this assay, with IC₅₀ values ranging from less than 0.05 μMto 10 μM.

Compound IC50 (μM) Example 1 <0.05 Example 2 0.15 Example 3 1.5 Example4 10 Example 6 <0.05 Example 7 <0.05 Example 8 <0.05 Example 9 1 Example12 0.15 Example 15 1 Example 17 10 Example 25 10 Example 30 1.5 Example31 0.5 Example 32 0.1

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1. A method of treating cancer or a cancerous condition, said method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a composition containing a compound of Formula I:

wherein: Y is —S(O)₂—; Z is (i) a substituent of the formula NR¹R², wherein R¹ and R² are independently selected from substituted or unsubstituted (C1-C10)alkyl, substituted or unsubstituted (C1-C10)alkoxyl, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C1-C4)alkyl, substituted or unsubstituted aryl-(C1-C4)alkoxy, substituted or unsubstituted aryl-(C1-C4)heteroalkyl, substituted or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted aryloxy-(C1-C4)alkyl, substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(C1-C4)alkyl, substituted or unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, and wherein NR¹R² are further connected by a linking group E to give a substituent of the formula

wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by R¹, E, R² and the nitrogen contains no more than 8 atoms; or (ii) a substituent of formula —NR^(a)R^(b) wherein R^(a) is H and R^(b) is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-(C1-C4)alkyl, substituted or unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl; with the proviso that R^(b) is not 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl; and that if R^(b) is 5-quinolyl or 4-pyridyl then R^(b) is substituted by at least one substituent that is not hydrogen; or a pharmaceutically acceptable salt of the compound.
 2. The method of claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein Z is a substituent of the formula

and the ring formed by N, R¹, E, R² contains 5 or 6 members.
 5. The method of claim 1, wherein the compound is selected from the group consisting of: 4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine; 4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine; 2-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidopyridine; 4-Pentafluorophenylsulfonamidopyridine; 1-Pentafluorophenylsulfonylindole; 1-Pentafluorophenylsulfonyl(2,3-dihydro)indole; 1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline; 1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline; 2-Chloro-5-pentafluorophenylsulfonamidopyridine; 5-Pentafluorophenylsulfonamidoindazole; 6-Pentafluorophenylsulfonamidoquinoline; 2,3-Dihydro-5-pentafluorophenylsulfonamidoindole; 5-Pentafluorophenylsulfonamidobenzo[a]thiophene; 5-Pentafluorophenylsulfonamidobenzo[a]furan; and 2-Anilino-3-pentafluorophenylsulfonamidopyridine, or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein Z is a substituent of the formula —NR^(a)R^(b) and R^(a) is H and R^(b) is monocyclic heteroaryl.
 7. The method of claim 1, wherein Z is a substituent of the formula —NR^(a)R^(b) and R^(a) is H and R^(b) is bicyclic heteroaryl.
 8. The method of claim 1, wherein Z is a substituent of the formula —NR^(a)R^(b) and R^(a) is H and R^(b) is selected from the group consisting of 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
 9. The method of claim 1, comprising inhibiting the growth of a target cell in the subject by contacting the cell with an effective amount of the compound, thereby treating or preventing the cancer or the cancerous condition.
 10. The method of claim 1, wherein the composition is administered orally.
 11. The method of claim 1, wherein the composition is administered intravenously.
 12. The method of claim 1, wherein the composition is administered intramuscularly.
 13. The method of claim 1, further comprising administration of a therapeutically effective amount of an antineoproliferative, chemotherapeutic, or cytotoxic agent that is not represented by formula I.
 14. The method of claim 1, wherein the compound is a prodrug.
 15. The method of claim 1, wherein the compound is conjugated to a targeting molecule which preferentially directs the compound to a targeted cell.
 16. The method of claim 13, wherein the antineoproliferative, chemotherapeutic, or cytotoxic agent is selected from the group consisting of cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, and hydroxyurea.
 17. The method of claim 1, wherein the subject is human.
 18. The method of claim 17, wherein the cancer is selected from the group consisting of Kaposi's sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, breast cancer, ovarian cancer, and lung cancer.
 19. The method of claim 1, wherein the cancer or cancerous condition is cancer.
 20. The method of claim 19, wherein the subject is human. 